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Obesity is associated with dysfunctions in hypothalamic neurons that regulate metabolism, including agouti-related protein (AgRP)-expressing neurons. In a recent article, Zhang et al. demonstrated that either diet- or genetically induced obesity promoted iron accumulation specifically in AgRP neurons. Preventing iron overload in AgRP neurons mitigated diet-induced obesity and related comorbidities in male mice.

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BACKGROUND AND AIMS: Patients with obesity and type 2 diabetes (T2D) have shown alterations in the affinity of IgG anti-leptin antibodies which are possibly related to metabolic alterations. In the present exploratory study, we analyzed serum samples from adults with T2D classified by body mass index (BMI) and evaluated the relationship of IgG anti-leptin antibodies with body composition, metabolic and cardiovascular risk parameters. METHODS: Serum IgG anti-leptin antibodies (total, free and immune complexes fractions) were measured by in-house ELISA. Body composition, metabolic biomarkers (glucose, glycated hemoglobin, lipid profile, insulin, leptin) and cardiometabolic risk indexes (AIP, HOMA-IR, HOMA-ß) were evaluated in one hundred T2D patients. RESULTS: Patients with T2D and obesity presented a decrease in the percentage of IgG anti-leptin immune complexes compared to patients with T2D and overweight (p < 0.0053). Negative correlations of IgG anti-leptin immune complexes with triglycerides (TG) (r=-0.412, p = 0.023) and VLDL-C (r=-0.611, p = 0.017) were found in normal weight T2D patients. Free IgG anti-leptin antibodies correlated positively with TC (r = 0.390, p = 0.032) and LDL-C (r = 0.458, p = 0.011) in overweight individuals with T2D. Finally, total IgG anti-leptin antibodies correlated positively with leptin hormone levels (r = 0.409, p = 0.024) and negatively with HOMA-IR (r =-0.459, p = 0.012) in T2D patients with obesity. CONCLUSIONS: The decrease of IgG anti-leptin immune complexes observed in patients with T2D and obesity suggests a reduction in antibody affinity to the hormone that may impact its transport and signaling, lipid, lipoprotein and insulin metabolism.

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At the time of its discovery and characterization in 1994, leptin was mostly considered a metabolic hormone able to regulate body weight and energy homeostasis. However, in recent years, a great deal of literature has revealed leptin's pleiotropic nature, through its involvement in numerous physiological contexts including the regulation of the female reproductive tract and ovarian function. Obesity has been largely associated with infertility, and leptin signalling is known to be dysregulated in the ovaries of obese females. Hence, the disruption of ovarian leptin signalling was shown to contribute to the pathophysiology of ovarian failure in obese females, affecting transcriptional programmes in the gamete and somatic cells. This review attempts to uncover the underlying mechanisms contributing to female infertility associated with obesity, as well as to shed light on the role of leptin in the metabolic dysregulation within the follicle, the effects on the oocyte epigenome, and the potential long-term consequence to embryo programming.

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At the time of its discovery and characterization in 1994, leptin was mostly considered a metabolic hormone able to regulate body weight and energy homeostasis. However, in recent years, a great deal of literature has revealed leptin's pleiotropic nature, through its involvement in numerous physiological contexts including the regulation of the female reproductive tract and ovarian function. Obesity has been largely associated with infertility, and leptin signalling is known to be dysregulated in the ovaries of obese females. Hence, the disruption of ovarian leptin signalling was shown to contribute to the pathophysiology of ovarian failure in obese females, affecting transcriptional programmes in the gamete and somatic cells. This review attempts to uncover the underlying mechanisms contributing to female infertility associated with obesity, as well as to shed light on the role of leptin in the metabolic dysregulation within the follicle, the effects on the oocyte epigenome, and the potential long-term consequence to embryo programming.(AU)

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The intermittent fasting (IF) might have benefits on metabolism and food intake. Twelve-week old C57BL/6 J mice were fed a control diet (C, 10% kcal fat), a high-fat diet (HF, 50% kcal fat) or a high-fructose diet (HFru, 50% kcal fructose) for 8 weeks, then half of the animals in each group underwent IF (24 h fed, 24 h fasting) for an additional 4 weeks. Although food intake on the fed day remained the same for all groups, all fasting groups showed a reduction in body mass compared to their counterparts. IF reduced total cholesterol, triacylglycerol, fasting glucose, fasting insulin resistance index, and plasma leptin, but increased plasma adiponectin. IF reduced Leptin gene expression in the HF-IF group, but increased proinflammatory markers in the hypothalamus, also in the C-IF group. Both groups HFru-IF and C-IF, showed alterations in the leptin signaling pathway (Leptin, OBRb, and SOCS3), mainly in the HFru-IF group, suggesting leptin resistance. NPY and POMC neuropeptides labeled the neurons of the hypothalamus by immunofluorescence, corroborating qualitatively other quantitative findings of the study. In conclusion, current results are convincing in demonstrating the IF effect on central regulation of food intake control, as shown by NPY and POMC neuropeptide expressions, resulting in a lower weight gain. Besides, IF improves glycemia, lipid metabolism, and consequently insulin and leptin resistance. However, there is increased expression of inflammatory markers in mouse hypothalamus challenged by the HF and HFru diets, which in the long term may induce adverse effects.

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Although novel pharmacological options for the treatment of type 2 diabetes mellitus (DM2) have been observed to modulate the functionality of several key organs in glucose homeostasis, successful regulation of insulin resistance (IR), body weight management, and pharmacological treatment of obesity remain notable problems in endocrinology. Leptin may be a pivotal player in this scenario, as an adipokine which centrally regulates appetite and energy balance. In obesity, excessive caloric intake promotes a low-grade inflammatory response, which leads to dysregulations in lipid storage and adipokine secretion. In turn, these entail alterations in leptin sensitivity, leptin transport across the blood-brain barrier and defects in post-receptor signaling. Furthermore, hypothalamic inflammation and endoplasmic reticulum stress may increase the expression of molecules which may disrupt leptin signaling. Abundant evidence has linked obesity and leptin resistance, which may precede or occur simultaneously to IR and DM2. Thus, leptin sensitivity may be a potential early therapeutic target that demands further preclinical and clinical research. Modulators of insulin sensitivity have been tested in animal models and small clinical trials with promising results, especially in combination with agents such as amylin and GLP-1 analogs, in particular, due to their central activity in the hypothalamus.

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The maternal organism undergoes numerous metabolic adaptations to become prepared for the demands associated with the coming offspring. These metabolic adaptations involve changes induced by several hormones that act at multiple levels, ultimately influencing energy and glucose homeostasis during pregnancy and lactation. Previous studies have shown that central growth hormone (GH) action modulates glucose and energy homeostasis. However, whether central GH action regulates metabolism during pregnancy and lactation is still unknown. In the present study, we generated mice carrying ablation of GH receptor (GHR) in agouti-related protein (AgRP)-expressing neurons, in leptin receptor (LepR)-expressing cells or in the entire brain to investigate the role played by central GH action during pregnancy and lactation. AgRP-specific GHR ablation led to minor metabolic changes during pregnancy and lactation. However, while brain-specific GHR ablation reduced food intake and body adiposity during gestation, LepR GHR knockout (KO) mice exhibited increased leptin responsiveness in the ventromedial nucleus of the hypothalamus during late pregnancy, although their offspring showed reduced growth rate. Additionally, both Brain GHR KO and LepR GHR KO mice had lower glucose tolerance and glucose-stimulated insulin secretion during pregnancy, despite presenting increased insulin sensitivity, compared with control pregnant animals. Our findings revealed that during pregnancy central GH action regulates food intake, fat retention, as well as the sensitivity to insulin and leptin in a cell-specific manner. Together, the results suggest that GH acts in concert with other "gestational hormones" to prepare the maternal organism for the metabolic demands of the offspring.

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Recent studies have highlighted the involvement of melatonin in the regulation of energy homeostasis. In this study, we report that mice lacking melatonin receptor 1 (MT1 KO) gained more weight, had a higher cumulative food intake, and were more hyperphagic after fasting compared to controls (WT). In response to a leptin injection, MT1 KO mice showed a diminished reduction in body weight and food intake. To evaluate hypothalamic leptin signaling, we tested leptin-induced phosphorylation of the signal transducer and activator of transcription 3 (STAT3). Leptin failed to induce STAT3 phosphorylation in MT1 KO mice beyond levels observed in mice injected with phosphate-buffered saline (PBS). Furthermore, STAT3 phosphorylation within the arcuate nucleus (ARH) was decreased in MT1 KO mice. Leptin receptor mRNA levels in the hypothalamus of MT1 KO were significantly reduced (about 50%) compared to WT. This study shows that: (a) MT1 deficiency causes weight gain and increased food intake; (b) a lack of MT1 signaling induces leptin resistance; (c) leptin resistance is ARH region-specific; and (d) leptin resistance is likely due to down-regulation of the leptin receptor. Our data demonstrate that MT1 signaling is an important modulator of leptin signaling.

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Leptin resistance refers to states in which leptin fails to promote its anticipated effects, frequently coexisting with hyperleptinaemia. Leptin resistance is closely associated with obesity and also observed in physiological situations such as pregnancy and in seasonal animals. Leptin resensitisation refers to the reversion of leptin-resistant states and is associated with improvement in endocrine and metabolic disturbances commonly observed in obesity and a sustained decrease of plasma leptin levels, possibly below a critical threshold level. In obesity, leptin resensitisation can be achieved with treatments that reduce body adiposity and leptinaemia, or with some pharmacological compounds, while physiological leptin resistance reverts spontaneously. The restoration of leptin sensitivity could be a useful strategy to treat obesity, maintain weight loss and/or reduce the recidivism rate for weight regain after dieting. This review provides an update and discussion about reversion of leptin-resistant states and modulation of the molecular mechanisms involved in each situation.

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OBJECTIVES: To compare the effects of a palatable cafeteria diet on serum parameters and neuroinflammatory markers of young and aged female Wistar rats. METHODS: Three-month-old (young) and 18-month-old (aged) female Wistar rats had access to a cafeteria diet (Caf-Young, Caf-Aged) or a standard chow diet (Std-Young, Std-Aged). RESULTS: The Caf-Young group showed a higher food consumption, weight gain, visceral fat depot, serum insulin and leptin levels, and the insulin resistance index (HOMA-IR) than the Std-Young group. The Caf-Aged group exhibited an increase in interleukin-1 levels in the cerebral cortex and hippocampus. The number of GFAP-positive cells did not differ between the groups, but there was a diet effect in the cerebral cortex and an age effect in the hippocampus. Phospho-tau expression did not differ between the groups. DISCUSSION: The 3- and 18-month-old rats responded differently to a cafeteria diet. Insulin and leptin levels are elevated in young animals fed a cafeteria diet, whereas aged animals are prone to neuroinflammation (indicated by an increase in interleukin-1ß levels). A combination of hypercaloric diet and senescence have detrimental effects on the inflammatory response in the brain, which may predispose to neurological diseases.

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Melatonin (Mel), a molecule that conveys photoperiodic information to the organisms, is also involved in the regulation of energy homeostasis. Mechanisms of action of Mel in the energy balance remain unclear; herein we investigated how Mel regulates energy intake and expenditure to promote a proper energy balance. Male Wistar rats were assigned to control, control + Mel, pinealectomized (PINX) and PINX + Mel groups. To restore a 24-h rhythm, Mel (1 mg/kg) was added to the drinking water exclusively during the dark phase for 13 weeks. After this treatment period, rats were subjected to a 24-h fasting test, an acute leptin responsiveness test and cold challenge. Mel treatment reduced food intake, body weight, and adiposity. When challenged to 24-h fasting, Mel-treated rats also showed reduced hyperphagia when the food was replaced. Remarkably, PINX rats exhibited leptin resistance; this was likely related to the capacity of leptin to affect body weight, food intake, and hypothalamic signal-transducer and activator of transcription 3 phosphorylation, all of which were reduced. Mel treatment restored leptin sensitivity in PINX rats. An increased hypothalamic expression of agouti-related peptide (Agrp), neuropeptide Y, and Orexin was observed in the PINX group while Mel treatment reduced the expression of Agrp and Orexin. In addition, PINX rats presented lower UCP1 protein levels in the brown adipose tissue and required higher tail vasoconstriction to get a proper thermogenic response to cold challenge. Our findings reveal a previously unrecognized interaction of Mel and leptin in the hypothalamus to regulate the energy balance. These findings may help to explain the high incidence of metabolic diseases in individuals exposed to light at night.

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Resumen La psoriasis es una enfermedad inflamatoria crónica que se distingue por hiperproliferación recidivante de la piel, de causa y patogénesis multifactoriales. Afecta aproximadamente a 1-3% de la población en general. Durante los últimos diez años, en diversos estudios se ha encontrado que los pacientes con psoriasis tienen prevalencia elevada de factores de riesgo cardiovascular. Asimismo, esos estudios también sugieren una relación entre el síndrome metabólico y la psoriasis. El síndrome metabólico comprende una serie de condiciones fisiopatológicas relacionadas principalmente con aspectos metabólicos, como la resistencia y señalización a la insulina y leptina (Sx Met_RI-Lep). Es un grupo de factores de riesgo que incluye obesidad central, dislipidemia aterogénica, hipertensión arterial sistémica e intolerancia a la glucosa. Su importancia se debe a que duplica el riesgo de enfermedad cardiovascular y diabetes mellitus tipo 2, y aumenta la mortalidad incluso más que sus componentes por separado. La prevalencia mundial del síndrome varía en función del país y de los criterios utilizados para medirla; varía entre 15 y 47% de la población general. Las prevalencias publicadas también varían de acuerdo con las organizaciones que las emiten; tal es el caso de los criterios de la Organización Mundial de la Salud (OMS), que indican que la prevalencia en México es de 14%, y al aplicar los criterios ATP-III asciende a 27%. Existen, por tanto, 6.7 y 14.3 millones de mexicanos afectados, según los criterios de la Organización Mundial de la Salud y los ATP-III, respectivamente. La asociación de la psoriasis con otras enfermedades sistémicas podría deberse a diversas causas, como predisposición genética, factores ambientales (tabaco, alcohol, vida sedentaria) o tratamientos sistémicos prescritos. Cada vez son más los estudios que relacionan el síndrome metabólico por resistencia a la insulina-leptina con la psoriasis. En esta revisión bibliográfica se pretende sintetizar los mecanismos fisiopatológicos compartidos por ambos padecimientos, así como insistir en el cribado de los factores de riesgo cardiovasculares y del síndrome metabólico para prevenir o mejorar el tratamiento y pronóstico de los pacientes con psoriasis.

Abstract Psoriasis is a chronic inflammatory disease characterized by relapsing skin hyperproliferation, with multifactorial pathogenesis and causes. It affects approximately 1% to 3% of the general population. During the past ten years, several studies have found that patients with psoriasis have a high prevalence of cardiovascular risk factors. Likewise, such studies also suggest a link between metabolic syndrome and psoriasis. Metabolic syndrome comprises a number of pathophysiologic conditions that mainly involves the metabolic aspects concerning insulin-leptin resistance and signaling (Sx Met_RI-Lep). It is a group of risk factors including central obesity, atherogenic dyslipidemia, systemic hypertension and glucose intolerance. Its importance is due to its presence doubles the risk of cardiovascular disease, type 2 diabetes mellitus and increases mortality higher than its separate components. The worldwide prevalence of the syndrome varies depending on the country and the criteria used; between 15% and 47% of the general population. The prevalence published also vary according to the organizations that issue; such is the case of the criteria of the World Health Organization (WHO) to handle a prevalence in Mexico of 14% and applying the criteria ATP-III rises to 27%, so there are 6.7 and 14.3 million Mexicans affected, according to the criteria of the World Health Organization and the ATP-III, respectively. The association of psoriasis with other systemic diseases may be due to various causes such as genetic predisposition, environmental factors (smoking, alcohol, sedentary lifestyle) or be influenced by systemic treatments used against psoriasis. More and more studies link the Sx Met_RI-Lep with psoriasis. This paper summarizes the pathophysiological mechanisms shared by both pathologies, as well as emphasizes screening for cardiovascular risk factors and metabolic syndrome to improve treatment and prognosis of psoriasis.

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Leptin is a permissive factor for the onset of puberty. However, changes in adiposity frequently influence leptin sensitivity. Thus, the objective of the present study was to investigate how changes in body weight, fatness, leptin levels and leptin sensitivity interact to control the timing of puberty in female mice. Pre-pubertal obesity, induced by raising C57BL/6 mice in small litters, led to an early puberty onset. Inactivation of Socs3 gene in the brain or exclusively in leptin receptor-expressing cells reduced the body weight and leptin levels at pubertal onset, and increased leptin sensitivity. Notably, these female mice exhibited significant delays in vaginal opening, first estrus and onset of estrus cyclicity. In conclusion, our findings suggest that increased leptin sensitivity did not play an important role in favoring pubertal onset in female mice. Rather, changes in pubertal body weight, fatness and/or leptin levels were more important in influencing the timing of puberty.

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OBJECTIVE: During pregnancy, women normally increase their food intake and body fat mass, and exhibit insulin resistance. However, an increasing number of women are developing metabolic imbalances during pregnancy, including excessive gestational weight gain and gestational diabetes mellitus. Despite the negative health impacts of pregnancy-induced metabolic imbalances, their molecular causes remain unclear. Therefore, the present study investigated the molecular mechanisms responsible for orchestrating the metabolic changes observed during pregnancy. METHODS: Initially, we investigated the hypothalamic expression of key genes that could influence the energy balance and glucose homeostasis during pregnancy. Based on these results, we generated a conditional knockout mouse that lacks the suppressor of cytokine signaling-3 (SOCS3) only in leptin receptor-expressing cells and studied these animals during pregnancy. RESULTS: Among several genes involved in leptin resistance, only SOCS3 was increased in the hypothalamus of pregnant mice. Remarkably, SOCS3 deletion from leptin receptor-expressing cells prevented pregnancy-induced hyperphagia, body fat accumulation as well as leptin and insulin resistance without affecting the ability of the females to carry their gestation to term. Additionally, we found that SOCS3 conditional deletion protected females against long-term postpartum fat retention and streptozotocin-induced gestational diabetes. CONCLUSIONS: Our study identified the increased hypothalamic expression of SOCS3 as a key mechanism responsible for triggering pregnancy-induced leptin resistance and metabolic adaptations. These findings not only help to explain a common phenomenon of the mammalian physiology, but it may also aid in the development of approaches to prevent and treat gestational metabolic imbalances.

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Therapies that improve leptin sensitivity have potential as an alternative treatment approach against obesity and related comorbidities. We investigated the effects of Socs3 gene ablation in different mouse models to understand the role of SOCS3 in the regulation of leptin sensitivity, diet-induced obesity (DIO) and glucose homeostasis. Neuronal deletion of SOCS3 partially prevented DIO and improved glucose homeostasis. Inactivation of SOCS3 only in LepR-expressing cells protected against leptin resistance induced by HFD, but did not prevent DIO. However, inactivation of SOCS3 in LepR-expressing cells protected mice from diet-induced insulin resistance by increasing hypothalamic expression of Katp channel subunits and c-Fos expression in POMC neurons. In summary, the regulation of leptin signaling by SOCS3 orchestrates diet-induced changes on glycemic control. These findings help to understand the molecular mechanisms linking obesity and type 2 diabetes, and highlight the potential of SOCS3 inhibitors as a promising therapeutic approach for the treatment of diabetes.

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O consumo materno de dieta hiperlipídica saturada durante a gestação e lactação favorece o desenvolvimento obesidade e anormalidades metabólicas na prole. Este trabalho teve como objetivo testar a hipótese de que a prole proveniente de mães alimentadas com dieta hiperlipídica durante a gestação e lactação desenvolve obesidade e anormalidades metabólicas e de que essas alterações estão associadas a resistência central a leptina. As ratas grávidas da linhagem C57BL/6 (n=20) foram alimentadas com dieta standard chow (SC; 19% de lipídeos) ou dieta hiperlipídica (HF; 49% de lipídeos) durante todo período de gestação e lactação. Após o desmame, a prole de machos foi dividida em quatro grupos experimentais, de acordo com a dieta das mães e da prole: SC(mães)/SC(prole), SC/HF, HF/SC e HF/HF (n=12/gp). As características metabólicas foram avaliadas pela curva de ganho de peso; medida da pressão arterial; glicose de jejum, área sob a curva no teste oral de tolerância a glicose; concentrações de triglicerídeos hepáticos e estimativa da esteatose hepática; análise plasmática de insulina e leptina e; distribuição e análise morfológica do tecido adiposo. Para analisar a sensibilidade a leptina, os quatro grupos originais foram subdivididos em dois grupos cada (veículo ou leptina-5µg) para verificar a resposta alimentar (g) após o tratamento agudo intracerebroventricular (ICV) e a sinalização hipotalâmica de leptina. A dieta HF durante o período pós-desmame (grupo SC/HF), durante gestação e lactação (grupo HF/SC), ou ambos os períodos (grupo HF/HF), promoveu aumento da massa corporal. No que concerne as alterações hepáticas e a ação da insulina, a dieta HF durante o período perinatal favoreceu 25% de esteatose hepática, hiperinsulinemia e hiperleptinemia, enquanto os demais grupos experimentais SC/HF e HF/HF, demonstraram um padrão mais exacerbado...

Maternal high-fat diet consumption during pregnancy and lactation causes metabolic abnormalities (MA) (similar to metabolic syndrome in humans) in the rodents’ offspring. We tested the hypothesis that the offspring of dams fed a high fat diet during pregnancy and lactation develop MA and leptin resistance.Pregnant C57BL6 mice (n=20) were fed either standard chow (SC; 19% fat) or a high fat diet (HF; 49% fat). After weaning, male offspring were divided into four groups according to the diet of dams and offspring: SC(dams)/SC(offspring), SC/HF, HF/SC and HF/HF (n=12/group). MA were characterized by weight gain curve measured weekly; tail-cuff systolic pressure; fast glucose and areas under the curve after oral glucose tolerance test; fat mass depots; leptin and insulin concentrations, all performed at 12 weeks of age.To analyze leptin sensitivity, each group was divided into two groups (vehicle or leptin-5µg) to identify the feeding response and pSTAT3 expression after acute intracerebroventricular (ICV) treatment (n=6/group). The HF schedule during post-weaning (SC/HF group), during gestation and lactation (HF/SC group), or both periods (HF/HF group), increased body mass in experimental groups. In respect to hepatic alterations and insulin action, the HF diet during gestation and lactation caused 25% of liver steatosis, hiperinsulinemia and hiperleptinemia, whereas SC/HF and HF/HF presented worst patterns. The fat distribution and morphometry pointed for the key role of HF during gestation and lactation in amplify the ability to store fat in the offspring...

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